Is MAP3K1 p.Arg339Trp (c.1015C>T) pathogenic?

MAP3K1 p.Arg339Trp (c.1015C>T) is classified Likely benign in MAP3K1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-09-08). AlphaMissense: likely pathogenic (0.9401); Ultra-rare (popmax 0.0165%, mid); Associated with 46,XY sex reversal 6.

What condition is associated with MAP3K1 p.Arg339Trp (c.1015C>T)?

MAP3K1 p.Arg339Trp (c.1015C>T) is associated with 46,XY sex reversal 6 (ClinVar).

How common is MAP3K1 p.Arg339Trp (c.1015C>T) in the general population?

MAP3K1 p.Arg339Trp (c.1015C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about MAP3K1 p.Arg339Trp (c.1015C>T)?

AlphaMissense predicts likely pathogenic (score 0.9401) — an in-silico prediction, not a clinical call.

MAP3K1 p.Arg339Trp

c.1015C>T · rs373572109 · VCV1049556

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9401 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

46,XY sex reversal 6

Computational evidence

Protein change
AlphaMissense	0.9401	likely pathogenic
REVEL	0.563	indeterminate
SaProt	LLR -11.81	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.27	donor loss · deltas
Constraint at this position
Conservation	phyloP 3.4	GERP 2.7, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 507 bp · p 3.3e-06 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,048 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00136% 22/1,613,918 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,048
East Asian	0.00891%	11,218
African / African-American	0.00267%	37,486
Admixed American	0.00167%	59,994
Finnishnot grpmax-eligible	0.00156%	63,990
European (non-Finnish)	0.0011%	90,766

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MAP3K1
Protein: p.Arg339Trp
Coding: c.1015C>T
MANE Select: NM_005921
dbSNP: rs373572109
Type: single nucleotide variant
Location: chr5:56864914 (GRCh38)
Gene constraint: LOEUF 0.355 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 1 PDB

Full MAP3K1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

46,XY sex reversal 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAP3K1 p.Arg339Gln Pathogenic ★ ⚠ same residue
MAP3K1 p.Arg186Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
MAP3K1 p.Ala594Ser Uncertain significance ★★ ⚠ same condition
MAP3K1 p.Arg204Lys Uncertain significance ★★ ⚠ same condition
MAP3K1 p.Gln548Glu Uncertain significance ★★ ⚠ same condition
MAP3K1 c.1035+12C>T Likely benign ★★ same condition
MAP3K1 c.1687-46C>G Benign ★★ same condition
MAP3K1 c.2179+16T>G Benign/Likely benign ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/map3k1-p-arg339trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown